1. Field of the Invention
The present invention relates to novel N-alkyl-N-phenylhydroxylamine compounds containing metal chelating groups, their preparation and pharmaceutical compositions containing the novel compounds as active ingredients, more particularly, to novel N-alkyl-N-phenylhydroxylamine compounds containing metal chelating groups, a process for preparing the same, the use of the novel compounds as therapeutics for treating and/or preventing various medical dysfunctions and diseases caused by reactive oxygen species (ROS) and/or excess Zn ions, in particular stroke, Parkinson's disease, and Alzheimer's disease.
2. Description of the Prior Art
According to Harman's free-radical theory of ageing, successive oxidation attacks create “oxidative stress” conditions, that is, create an imbalance between the protective systems in favour of the pro-oxidants. Such attacks result in numerous molecular modifications, especially of polyunsaturated membrane lipids, proteins and nucleic acids. Human and animal organisms possess various defense mechanisms that act in synergy. Those mechanisms are of an enzymatic nature (superoxide dismutase, catalase, and glutathione peroxidase) or of a non-enzymatic nature (such as vitamins E and C, which enable physiological control of free-radical activity). With ageing, however, that protection becomes less efficient, not to say inefficient, especially as a result of the decreased activity of a large number of enzymes including those involved in such defense mechanisms. Consequently, for some disorders associated with ageing, such as atherosclerosis, cataract, non-insulin-dependent diabetes, cancer or chronic neurodegenerative disorders, numerous studies have been able to demonstrate that such conditions are associated with those “oxidative stress” conditions.
The central nervous system is especially sensitive to “oxidative stress” because of its high oxygen consumption, the relatively low levels of its antioxidant defenses and the high iron concentration of some cerebral regions. This explains why “oxidative stress” might be one of the main etiological factors of cerebral ageing, as well as of acute central nervous system disorder such as stroke, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and neurodegeneracies of the basal ganglia. The rate of occurrence of neurodegenerative disorders of central nervous system increases worldwide. Stroke occupies the third highest cause of death following cardiovascular diseases and malignant tumors (see: Parnetti, L. et al., Drug, 53:752 (1997)).
Antioxidants protecting neuron cells of brain from oxidative stress include vitamin E derivatives such as Trolox (see: J. Med. Chem., 38:453 (1995)), glutathione peroxidase (hereinafter, referred to as “GPx”) mimics (see: Daiichi Pharmaceutical Co., Ltd., Annual Report (1999); WO 9808831; U.S. Pat. No. 5,008,394; J. Am. Chem. Soc., 119:2079-2083 (1997); Adv. Pharmacol., 38:229 (1996)), superoxide dismutase (SOD) mimics (see: U.S. Pat. No. 5,827,880), and spin trapping agents (see: J. Med. Chem., 39:4988 (1996); U.S. Pat. No. 5,475,032).
A GPx mimic is synthesized compound mimicking the function of the selenocystein from GPx active site. A well-known GPx mimic, Ebselen seems to have no major toxicity in preclinical and clinical tests and it is proposed as a potential drug for stroke. Ebselen is, however, very little soluble in water, even in the presence of an excess of glutathione (GSH), which limits its pharmacological applications.
Spin trapping agents may be developed as an antioxidant if they can trap hazardous free radicals enough, which include α-phenyl-N-tert-butylnitrone (PBN), and various derivatives of PBN have been developed. Generally, nitrone moiety increases the solubility of compounds in water. However, it has revealed shortcomings such as a low lipid peroxidation inhibition activity in vitro and a low protection of brain cells in vivo (see: Fevig, Thomas L. et al., J. Med. Chem., 39:4988-4996 (1996)).
On the other hand, zinc ion, which is present with high concentration (>10 mM) in synaptic vesicle storing brain neurotransmitters, is a necessary element in normal function of human cells. As soon as a neuron is stimulated, zinc ion is released into interstitial fluid and then plays a crucial role in signal transmission from neuron to neuron, especially signal transmission by glutamate.
Furthermore, a variety of studies have reported that zinc ion in the synapse may play a central role in the pathological phenomena of central nervous system. The exposure of brain cortex neuron cells to excess zinc results in the immediate neuron cell injury, while the concentration of zinc is similar to that of zinc released from the brain in convulsion or ischemia. Hence, zinc is supposed to evoke neuron cell injury, by way of the influx of excess zinc into neuron cells. In accordance with the above hypothesis, it was found that translocation of synapse zinc in neuron cells was a main cause of selective neuronal cell injury after transient global cerebral ischemia, rather than excitotoxicity by calcium (see: Koh, J.-Y. et al, Science, 272:1013-1016 (1996); Kim, Y.-H. et al, Neuroscience, 89: 175-182 (1999)). It is, more plausible that the neurotoxicity by the translocation of zinc may play a central role in acute neuron cell death derived from focal ischemia. Therefore, the chelation of zinc is supposed to be effective on persisting protection of neuron cells. However, the zinc chelator for the treatment and prevention of neurodegenerative disease of central nervous system is not developed yet.